The present invention relates to novel tricyclic compounds which strongly antagonize an action of thromboxane A.sub.2 (hereafter referred to as TXA.sub.2).
It is hitherto known that TXA.sub.2 strongly aggregates platelets and is a potent vasoconstrictor [cf. Arachidonic Acid Cascade and Drugs, edited by Shozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1958)]. Further TXA.sub.2 is a powerful vasoconstrictor against bronchus and bronchial smooth muscle. Therefore, TXA.sub.2 is considered to take part in pathological conditions over a wide range. The following diseases can be exemplified.
(1) Ischemic disease PA0 (2) Cerebro-vascular disease PA0 (3) Peripheral vascular diseases and disease caused by unbalanced lipid. PA0 (4) Inflammatory and allergic diseases PA0 (5) Shock PA0 (6) Cancer metastasis PA0 ------ represents a single bond or a double bond; W represents --S--, --O--, --NH--, --CH.sub.2 --, --NHCO-- or .dbd.CH-- (wherein the left side of each formula is bound to the mother nucleus); n is 0, 1, 2 or 3; PA0 Z represents --NR.sup.1 CO--, NR.sup.1 SO.sub.2 --, NR.sup.1 CONH--, --NR.sup.1 CSNH--, --NR.sup.1 NHCONH--, --NR.sup.1 NHCSNH--, --NR.sup.1 COO-- or --NR.sup.1 COS-- (wherein R.sup.1 represents hydrogen or lower alkyl, in which the right side of each formula is bound to Q); PA0 Q represents straight or branched alkyl having 1 to 18 carbon atoms, alicyclic alkyl having 3 to 6 carbon atoms, lower alkenyl having 2 to 6 carbon atoms, or optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aromatic heterocyclic group [the group represents furyl, thienyl, N-substituted or unsubstituted pyrrolyl (the N-substituent is selected from lower alkyl, phenyl and benzyl), pyridyl, quinolyl or isoquinolyl] or coumarinyl; wherein the substitution means that with 1 to 3 substituents onto the aromatic ring and the substituent is independently selected from lower alkyl, phenyl, benzyl, halogen, trifluoromethyl, nitro, OR.sup.2 and SR.sup.2 (wherein R.sup.2 represents hydrogen, lower alkyl, phenyl or benzyl); PA0 one of R.sup.A and R.sup.B represents hydrogen and the other represents --Y--M [wherein Y represents single bond, --CR.sup.3 R.sup.4 --(CH.sub.2).sub.m -- or --CR.sup.3 .dbd.CR.sup.4 --(CH.sub.2).sub.m -- (wherein each of R.sup.3 and R.sup.4 independently represents hydrogen or lower alkyl and m represents 0, 1, 2, 3 or 4, in which the left side of each formula is bound to the mother nucleus); M represents --COOR.sup.5 (wherein R.sup.5 represents hydrogen or lower alkyl), --CONR.sup.5a R.sup.5b (wherein in each of R.sup.5a and R.sup.5b independently has the same significance for R.sup.5 as described above) or tetrazolyl]; each of G.sup.A and G.sup.B independently represents lower alkyl, halogen or OR.sup.6 (wherein R.sup.6 represents hydrogen, lower alkyl, phenyl or benzyl); PA0 each of g.sup.A and g.sup.B independently represents 0, 1, 2 or 3; and a pharmaceutically acceptable salt thereof. PA0 [Synthesis of Compound (Ia) in Compound (I), wherein W is W.sub.a and Z is --NR.sup.1 SO.sub.2 - (part 1)] ##STR10## wherein W.sub.a represents --S--, --O-- or --NH--; and X.sub.1 -X.sub.2, L, R.sup.A R.sup.B, G.sup.A, G.sup.B, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above. PA0 [Synthesis of Compound (Ia) (part 2)] PA0 [Synthesis of Compound (Ib) in Compound (I), wherein W is --NHCO-- and Z is --NR.sup.1 SO.sub.2 ] ##STR21## wherein X.sub.1 -X.sub.2, L, R.sup.A, R.sup.B G.sup.A, G.sup.B, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above. PA0 [Synthesis of Compound (Ic) in Compound (I), wherein W is .dbd.CH-- and Z is --NR.sup.1 SO.sub.2 --] ##STR26## wherein X.sub.1 -X.sub.2, L R.sup.A, R.sup.B, G.sup.A, G.sup.B R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above. PA0 [Synthesis of Compound (Ic-1) in Compound (Ic), wherein n is 1] ##STR35## wherein X.sub.1 -X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, R.sup.1, Q, g.sup.A and g.sup.B have the same significances as described above. PA0 [Synthesis of Compound (Id) in Compound (I), wherein W is Wb and Z --NR.sup.1 CO--] ##STR42## wherein Wb represents --S--, --O--, --NH--, --NHCO-- or .dbd.CH--; and ------, X.sub.1 -X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above. PA0 [Synthesis of Compound (Ie) in Compound (I), wherein W is Wb and Z is ##STR45## wherein ------, X.sub.1 -X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B Wb, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above and E represents oxygen or sulfur. PA0 [Synthesis of Compound (If) in Compound (I), wherein W is Wb and Z is ##STR48## wherein ------, X.sub.1 -X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, Wb, R.sup.1, E, Q, n g.sup.A and g.sup.B have the same significances as described above. PA0 [Synthesis of Compound (Ig) in Compound (I), wherein W is Wb and Z is ##STR51## wherein ------, X.sub.1 -X.sub.2, L, R.sup.A, G.sup.A, G.sup.B, Wb, R.sup.1, E, Q, n, g.sup.A and g.sup.B have the same significances as described above. PA0 [Synthesis of Compound (Ih) in Compound (I), wherein W is --CH.sub.2 --] ##STR54## wherein X.sub.1 -X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, Z, Q, n, g.sup.A and g.sup.B have the same significances as described above. PA0 [Synthesis of Compound (I-1) in Compound (I), wherein M is --COOH] ##STR57## wherein one of R.sup.A1 and R.sup.B1 represents --Y--COOH and the other represents hydrogen; and ------, X.sub.1 -X.sub.2, L, G.sup.A, G.sup.B, Y, W, Z, Q, n, g.sup.A and g.sup.B have the same significances as described above.
For example, myocardial infarction, angina pectoris, and thrombosis
For example, transient ischemic attack, migraine, cerebral hemorrhage, and cerebral infarction, PA1 For example, atherosclerosis, capillary convulsion, peripheral circulation disorders, hypertension, and pulmonary embolism PA1 For example, bronchial asthma, bronchitis, pneumonia, nephritis, and hepatitis
Accordingly, compounds that antagonize the action
of TXA.sub.2 are expected to have therapeutic effects in preventing or treating one or more of the diseases described above or other diseases involving TXA.sub.2. Further where in drugs used for medical purposes heretofore, application thereof is limited due to side effects mediated by TXA.sub.2 or assumed to be mediated by TXA.sub.2, it is expected to alleviate the side effects by the use of compounds which antagonize the action of TXA.sub.2.
As an antagonist of TXA.sub.2, representative compounds are exemplified in Thrombosis Research, 44, 377 (1986). Furthermore, an indole compound having the following structure: ##STR2## etc. is disclosed in Japanese Published Unexamined Patent Application No. 249960/1986 [West German Patent Application (DE) No. 3,514,696] and a compound having the following structure: ##STR3## is disclosed in Japanese Published Unexamined Patent Application No. 212552/1986 [West German Patent Application (DE) No. 3,508,692]. These compounds are derivatives having a phenylsulfonamide group and exhibit an activity of antagonizing TXA.sub.2.
On the other hand, among tricyclic compounds represented by the following formula: ##STR4## wherein L is --CH.dbd.CH--, R.sup.o as a substituent on the aromatic ring has carboxyl or a derivative thereof (for example, an ester, an amide, etc.; hereafter collectively referred to as carboxylic acid group) directly or via an alkylene chain, etc. and W.sup.o is hydrogen or a substituent such as oxo (.dbd.O), methylene (.dbd.CH.sub.2), hydroxyl, alkoxyl, etc., oxepine 5 derivatives wherein X.sub.1 -X.sub.2 =--CH.sub.2 O--, are known to show antiinflammatory, antiallergic activities, etc. [J. Med. Chem., 19, 941 (1976); ibid. 20, 1499 (1977); ibid, 21, 633 (1978); U.S. Pat. No. 4,282,365 (Japanese Published Unexamined Patent Application No. 21679/1983); U.S. Pat. No. 4,585,788; Japanese Published Unexamined Patent Application Nos. 152673/1986; 152674/1986 and 152675/1986]. Further, it is also known that oxepine derivatives wherein R.sup.o is hydrogen or a substituent other than the carboxylic acid group, such as alkyl, alkoxyl, halogen, etc. and W.sup.o has an alkylaminoalkyl chain via hetero atom (--NH--, --O--, --S--, etc.) show antihistaminic, antiallergic, antiasthmatic, activities, etc. [Japanese Published Unexamined Patent Application Nos. 150083/1981 (U.S. Pat. Nos. 4,396,550 and 4,465,835); 139073/1982; 126883/1983 (EP 0085870A) and 227879/1984] . It is also known that derivatives such as oxepine or thiepine (wherein X.sub.1 -X.sub.2 is --CH.sub.2 S--) wherein W.sup.o is alkylaminoalkylidene show an antidepressant action, etc. [U.S. Pat. Nos. 3,354,155 and 3,420,851; Drugs, 13, 161 (1977); Arz.-Forsch., 13, 1039 (1963); ibid., 14, 100 (1964)]. Furthermore, it is known that derivatives such as cycloheptene (wherein X.sub.1 -X.sub.2 is --CH.dbd.CH--) or thiepine wherein W.sup.o has an alkyl chain substituted with an alicyclic nitrogen-containing heterocyclic group such as piperazine, etc. at the terminal thereof via --NHCO-- have a calcium antagonizing activity [Japanese Published Unexamined Patent Application Nos. 47466/1986 (U.S. Pat. No. 4,749,703) and 153280/1987].
Further oxepine derivatives having an antiallergic activity wherein R.sup.o has carboxylic acid group and W.sup.o has an alkylaminoalkyl chain via a hetero atom are known [Japanese Published Unexamined Patent Application Nos. 28972/1985 (U.S. Pat. No. 4,596,804); 152669/1986; 152670/1986 152671/1986; 152672/1986 (all of them correspond to EP 188802 A); 152676/1986 and 257981/1986]. Furthermore, oxepine or cycloheptene (wherein X.sub.1 -X.sub.2 =--CH.sub.2 CH.sub.2 --) derivatives showing an antihistaminic activity wherein W.sup.o is alkylaminoalkylidene are known [Japanese Published Unexamined Patent Application No. 45557/1987 (EP 214779A)].
In addition, thienobenzoxepine and thiepine derivatives showing an antiinflammatory activity wherein L is --S--, R.sup.o has carboxylic acid group and W.sup.o is oxo are disclosed in J. Med. Chem., 21, 633 (1978) supra.